Pulmonary macrophages may be the most important primary defense system protecting the lungs from microbial invasions as well as from neoplastic growth. These cells also interact with lung epithelium, fibroblasts and lymphocytes. The germfree colostrum-deprived immunologically "virgin" piglets have absolutely no resident pulmonary alveolar macrophages. Therefore, the gnotobiotic piglet model presents a unique opportunity to investigate: 1) Ontogenic development and differentiation of resident pulmonary alveolar macrophages in a controlled environment starting from the zero level; 2) characterization of resident pulmonary alveolar macrophages at different stages of differentiation; 3) functional role of pulmonary alveolar macrophages including cytostasis, spontaneous cytotoxicity, antibody-dependent cellular cytotoxicity, complement (C3)-dependent cellular cytotoxicity; regulatory function on natural killer cell activity; effects on primary and secondary antibody responses; effects on mixed lymphocyte culture reaction, cytotoxic T lymphocyte response, autologous-mixed lymphocyte reaction and mitogenic responses to various mitogens; antineoplastic effects and interactions between pulmonary alveolar macrophages and lymphocytes, fibroblast and epithelial cells; 4) mechanism of self/nonself-recognition and autoreactivity; and 5) factors influencing the development and differentiation of pulmonary alveolar macrophages and factors affecting their effector functions against target cells. Investigations on ontogenic development, differentiation, and functions of pulmonary alveolar macrophages and regulatory mechanisms of their cytolytic and cytostatic effector functions may eventually lead to manipulation or control of pulmonary alveolar macrophages against invading cells to confer on the host a better survival advantage.